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At least 19 recordsLinked to original sources
PubMed2005

Reaction of 2-methoxy-3H-azepine with NBS: efficient synthesis of 2-substituted 2H-azepines.

[reaction: see text] The reaction of 2-methoxy-3H-azepines, in the presence or absence of a nucleophile, with N-bromosuccinimide (NBS) gave a regioselective 1,4-adduct from which the corresponding 2H-azepine derivatives were formed via base-promoted hydrogen bromide elimination, generally in moderate to quantitative yield. Competitive formation of 4-bromo-2-methoxy-3H-azepine by electrophilic substitutuion or 3H-azepin-2-yl 2H-azepin-2-yl ether by transetherification was minimized at lower reaction temperatures. Quantitative substitution of 2-(2',4',6'-trichlorophenoxy)-2H-azepine derivatives, formed in moderate yield from the respective 3H-azepine and NBS in the presence of 2,4,6-trichlorophenol (TCP), by various nucleophiles gave the corresponding 2-substituted 2H-azepine. Among these nucleophiles were alkanethiol and alkylamine that are not tolerated in the reaction of 3H-azepine and NBS.

Journal Article↗
PubMed1990

The anti-inflammatory activity of 5H-dibenz[c,e]azepine-5,7(6H)dione, 6,7-dihydro-5H-dibenz[c,e]azepine, N-benzoylbenzamide and 1H-benz[d,e]isoquinoline-1,3(2H)dione derivatives in rodents.

A series of N-substituted 5H-dibenz[c,e]azepin-5,7(6H)dione, 6-substituted 6,7-dihydro-5H-dibenz[c,e]azepine, 1H-benz[d,e]isoquinoline-1,3(2H)dione and N-benzoyl derivatives was shown to have anti-inflammatory and local analgesic activity in rodents. 6-(4-Chlorophenyl)-5H-dibenz[c,e]azepin-5,7(6H)dione demonstrated greater than 50% inhibition of induced edema and the writhing reflex at 25 mg/kg, I.P. in mice. 6-Methyl-6,7-dihydro-5H-dibenz[c,e]azepine and the N-butyl and N-pentyl derivatives of the dibenz-[c,e]azepine and N-benzoylbenzamide series demonstrated potent activity in both screens. The 1H-benz[d,e]isoquinoline-1,3(2H)diones were generally less active than the other three chemical classes of agents tested. However, the 2-(methylthio)ethyl derivative of this series demonstrates good activity in both screens. These agents appeared to be as potent as the standards, indomethacin and phenylbutazone, as anti-inflammatory agents in these animal models. Selected agents, e.g. 6-(4-methylphenyl)-5H-dibenz[c,e]azepin-5,7(6H)dione demonstrated anti-arthritic and anti-gout activities in rodents. The N-methyl and N-butyl derivatives of 6,7-dihydro-5H-dibenz[c,e]azepine afforded good anti-pleurisy activity in rats at 25 mg/kg x 2. The agents which demonstrated potent anti-inflammatory action were found to inhibit acid lysosomal hydrolytic enzyme activities in mouse liver and macrophages at 10(-5) M concentrations. Trypsin, elastase and collagenase activities were also inhibited by the derivatives. Prostaglandin synthetase activity of bovine seminal vesicles and mouse macrophages was inhibited by the compounds at 10(-5) M concentrations.

Animals↗
PubMed2000

Selenium dioxide oxidations of dialkyl-3H-azepines: the first synthesis of 2-azatropone from oxidation of 2, 5-Di-tert-butyl-3H-azepine

Oxidation reactions of 2,5- and 3,6-di-tert-butyl-3H-azepines (1 and 2) with selenium dioxide (SeO(2)) were performed. The oxidation of 1 with SeO(2) gave 3-tert-butyl-7,7-dimethyl-4-oxo-octa-2,5-dienal 3 in 36% yield, 4-tert-butyl-5-(3,3-dimethyl-2-oxo-butylidene)-1, 5-dihydro-pyrrol-2-one 4 in 13% yield, 2, 6-di-tert-butyl-2-pyridinecarbaldehyde 5 in 12% yield, and 4, 7-di-tert-butyl-2H-azepin-2-one (2-azatropone) 6 in 6% yield, respectively. Oxidation of 2 with SeO(2) gave 2, 2-dimethyl-1-[2-(5-tert-butyl)-pyridyl]propanol 7 in 55% yield, and 3,6-di-tert-butyl-2H-azepine 8 in 5% yield, respectively. We found that selenium dioxide oxidation of 1 affords 4-oxo-octa-2,5-dienal 3 by a new ring cleavage reaction of 1, and we described the first synthesis of 2-azatropone 6 from this oxidation of 1. In the case of 2, pyridylpropanol 7 was obtained as the major product. We now report in detail result of these oxidation reactions, which have led to the synthesis of a novel azatropone derivative.

Journal Article↗
PubMed1979

[Derivatives of 2,3,4,5,-tetrahydro-1H-pyrido-(3,2-b)azepine and 2,3,4,5-tetrahydro-1H-pyrido(2,3-b)azepine and their corresponding lactams. II. Synthesis and pharmacologic study of their psychotropic activity].

Preparation of the N-(2-diethylaminoethyl) derivatives of lactam (II) and of the N-(3-dimethylaminopropyl) derivative of lactam (XI) is described. Synthesis of the N-[4-(2-hydroxyethyl)piperazinylacetyl]- and 1-carbothiamide derivatives of azepine (I) and of the n-(chloroformyl)- and N-(carbamoyl) derivatives of azepine (XII) are also described. Some pharmacological results indicate a partial tranquilizing activity.

Animals↗
PubMed1986

Hypolipidemic activity of 6-substituted 6,7-dihydro-5H-dibenz[c,e]azepine and the effects of 6,7-dihydro-5H-dibenz[c,e]azepine on lipid metabolism of rodents.

A series of 6-substituted derivatives of 6,7-dihydro-5H-dibenz[c,e]azepine was found to be active hypolipidemic agents in rodents at doses of mg/kg per day. The parent drug was found to suppress the enzyme activity of ATP-dependent citrate lyase, sn-glycerol-3-phosphate acyl transferase, and phosphatidate phosphohydrolase. Treatment with 6,7-dihydro-5H-dibenz[c,e]azepine resulted in a reduction of cholesterol, neutral lipid, and triglyceride content in mouse and rat liver. The agent also afforded a reduction in cholesterol, triglycerides and neutral lipids in the chylomicron and very low density lipoprotein (VLDL) fractions. In the high density lipoprotein (HDL) fraction, the triglyceride, neutral lipids, and phospholipids were lowered but the cholesterol content was not. [H3]Cholesterol distribution studies showed that the 3H-content was lowered in the major organs but was elevated in the chyme and stomach, suggesting that the drug accelerated bile secretion of cholesterol or its metabolites.

Animals↗
PubMed1993

Comparison between 6,7-dihydro-5H-dibenz(c,e)azepine and lovastatin as hypolipidemic agents in rats.

6,7-Dihydro-5H-dibenz(c,e)azepine (azepine) and lovastatin were investigated for their hypolipidemic activity in Sprague-Dawley male rats. Azepine lowered both serum total cholesterol and serum triglyceride levels, whereas lovastatin only lowered serum total cholesterol levels significantly. Lovastatin also elevated lipid levels in tissues, whereas azepine in general did not have a similar effect. High-density lipoprotein cholesterol levels were significantly elevated and low-density lipoprotein cholesterol levels were reduced after treatment with both agents. Concentrations of ApoE and ApoAl of high-density lipoprotein were increased after treatment, a result that should enhance the reverse cholesterol transport process of returning cholesterol to the liver for excretion. Azepine appeared to be safe in its therapeutic range in rodents.

Administration, Oral↗
PubMed1985

Effects of some dibenzo-azepines on suppressed and nonsuppressed behavior of squirrel monkeys.

Six dibenzo-azepine derivatives were compared for their effects on suppressed and nonsuppressed behavior of squirrel monkeys. Monkeys responded by pressing a lever under a two-component fixed-ratio schedule of food presentation in which responding in one component was suppressed by response-produced electric shock. Intermediate doses (0.3-1.0 mg/kg IM) of selected unsubstituted and 8-chlorine-substituted dibenzo-azepines (perlapine, 106-094, and clozapine) increased responding that was suppressed by electric shock, whereas selected 2-chlorine-substituted dibenzo-azepines (loxapine, clothiapine, and 105-056) did not consistently increase suppressed responding at any dose (0.001-0.1 mg/kg IM). All six dibenzo-azepines decreased nonsuppressed responding in a dose-related manner, with the 2-chlorine-substituted derivatives being 16-50 times more potent than their unsubstituted or 8-chlorine-substituted congeners. These structure-activity relationships indicate that the effects of the dibenzo-azepines on both suppressed and nonsuppressed behavior differ qualitatively depending on the location of the chlorine substituent.

Animals↗
PubMed1986

Tricyclic epines. Novel (E)- and (Z)-11H-dibenz[b,e]azepines as potential central nervous system agents. Variation of the basic side chain.

The synthesis and pharmacological activity of new (E),(Z)-[6-(alkylamino)-11H-dibenz[b,e]azepin-11- ylidene]acetonitriles 12-45 and (E),(Z)-[6-(aminoalkoxy)-11H-dibenz[b,e]azepin-11-ylidene] acetonitriles 46-51 are described. The introduction of the cyanomethylene group into the 11-position of the 11H-dibenz[b,e]azepine framework has been carried out by a Wittig-Horner reaction under mild conditions. The (E),(Z) isomers were separated by fractional crystallization, assignment being achieved by X-ray analysis. A number of (E),(Z)-[6-(alkylamino)-11H-dibenz-[b,e]azepin-11-ylidene] acetonitriles (12, 14, 16, 20) show potent neuroleptic activity (2-7 times that of clozapine) in animal tests. The screening included tests for sedative and anticholinergic activity in mice, apomorphine and tryptamine antagonism in rats, and muscle-relaxing activity in rabbits. The divergence in the activity profile in the case of the separated (E),(Z) isomers has been observed as an interesting new aspect: the (Z) isomers show a significantly higher sedative and muscle-relaxant activity, whereas the (E) isomers possess a higher anticholinergic efficacy and somewhat greater apomorphine antagonism. Broad changes in the basic side chain were made in order to investigate structure-activity relationships. The important geometrical parameters for the molecules, obtained by X-ray analysis, were compared with the corresponding features in dopamine agonists and antagonists.

Animals↗
PubMed2000

Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo[3,2-c]azepines and related compounds.

A series of 5-aminoalkylpyrrolo[3,2-c]azepine derivatives was synthesized and their serotonin 2 (5-HT2) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT2 receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as the aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring. Compound 18a, 5-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl- 1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as having potent 5-HT2 receptor antagonist activity with weak alpha1 adrenoceptor blocking activity and no significant D2 receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed only weak 5-HT2 receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174) displayed the overall best profile with potent 5-HT2 receptor antagonist activity (pA2=8.98+/-0.06) and high selectivity versus other receptors. SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC50=6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

Practical stereoselective synthesis of (2,3,4, 5-tetrahydro-1H-benzo[b]azepin-5-yl)acetic acid.

Highly enantioselective asymmetric hydrogenation of readily accessible olefins, (E)- and (Z)-[1-(toluene-4-sulfonyl)-1,2,3, 4-tetrahydro-1H-benzo[b]azepin-5-ylidene]acetic acid (4a and 4b, respectively) and [1-(toluene-4-sulfonyl)-2, 3-dihydro-1H-benzo[b]azepin-5-yl]acetic acid (4c), is presented as an efficient and straightforward route to (R)-[1-(toluene-4-sulfonyl)-2,3,4, 5-tetrahydro-1H-benzo[b]azepin-5-yl]acetic acid [(R)-1] which is a key intermediate for the synthesis of non-peptide AVP V2-agonist. Hydrogenation of carboxylic acid 4c gave (R)-1 in quantitative yield and 85% ee using Ru(OAc)2[(S)-H8-BINAP], a Ru(II) complex of a partially hydrogenated BINAP (H8-BINAP), as a catalyst. When (R)-1 of 76% ee was transformed into the corresponding isopropylamide 6, pure enantiomer (R)-6 was obtained in 75% yield by recrystallization from MeOH.

Journal Article↗
PubMed1977

Epoxide-diol pathway in the metabolism of 5H-dibenzo[b,f]-azepine (iminostilbene).

5H-Dibenzol[b,f]azepine-10,11-epoxide and 10,11-dihydro-10,11-dihydroxy-5H-dibenzo[b,f]azepine were identified by gas chromatography-mass spectrometry in rat urine as the main biotransformation products in the metabolism of 5H-dibenzo[b,f]azepine (iminostilbene). The presence of these metabolites was confirmed in vitro by incubating iminostilbene with rat liver microsomal enzymes.

Alcohols↗
PubMed1985

[New derivatives of 10,11-dihydro-5H-dibenz[b,f]azepine with antiarrhythmic action].

After an introduction about the importance of the 10, 11-Dihydro-5H-dibenz[b,f]azepine system for the drug research and according to experiences about the change of pharmacodynamic effects in the field of the phenothiazine bases by dialkylaminoacyl substitution in the following report some new 3-carbalkoxyamino-5-omega-aminoacyl-10,11-dihydro-5H-dibenz[b,f]++ +azepines and their intermediates for synthesis are described. In result of pharmacological investigations which showed antiarrhythmic activities the substance 3-carbethoxyamino-5-dimethylaminoacetyl-10,11-Dihydro-5H-dib enz[b, f]azepine X HCl (GS 015, AWD 19-166, Bonnecor) was selected for clinical tests. For studying the biotransformation of this substance the expected main metabolites were prepared by chemical synthesis.

Animals↗
PubMed2000

The synthesis and vasopressin (AVP) antagonist activity of a novel series of N-aroyl-2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepines.

Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.

Animals↗
PubMed1975

Synthesis of thieno[2,3-b]azepin-4-ones as potential antineoplastic agents.

In view of the antitumor activity reported for 7,8-dimethylbenzo[b]azepine-2,5-dione, new isosteric thieno[2,3-b]-azepin-4-ones have been prepared by a Dieckmann ring closure reaction. Substituted 2-amino-3-carbethoxythiophenes were tosylated, or benzoylated, and the corresponding sodium salt was alkylated with ethyl 4-bromobutyrate. The resulting product was cyclized in the presence of sodium hydride, and the azepinones were detosylated with 40% sulfuric acid-acetic acid solution. Preliminary biological data do not indicate any siginificant antineoplastic activity.

Animals↗
PubMed1999

Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives.

A series of esters of the major metabolite of oxcarbazepine (2), 10, 11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED(50) values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 0.9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b, f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1 produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7, and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED(50) value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [(3)H]batrachotoxinin A 20-alpha-benzoate ([(3)H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and 2 at inhibiting the binding of [(3)H]BTX to sodium channels and the influx of (22)Na(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.

Amides↗
PubMed2004

Phytochemical and larvicidal studies on Stemona curtisii: structure of a new pyrido[1,2-a]azepine Stemona alkaloid.

A new pentacyclic Stemona alkaloid, stemocurtisinol (3), with a pyrido[1,2-a]azepine A,B-ring system, and the known pyrrolo[1,2-a]azepine alkaloid oxyprotostemonine (4) have been isolated from a root extract of S. curtisii. The structure and relative stereochemistry of stemocurtisinol was determined by spectral data interpretation and X-ray crystallography. This compound is a diastereoisomer of oxystemokerrin and has the opposite configuration at C-4 and C-19. The individual alkaloid components showed significant larvicidal activity (IC(50) 4-39 ppm) on mosquito larvae (Anopheles minimus HO).

Alkaloids↗
PubMed2000

Studies on antihypertensive agents with antithrombotic activity. 2. Syntheses and pharmacological evaluation of pyrrolo[2,3-c]azepine derivatives.

As an extension of our previous investigation, a series of 7-aminoalkylpyrrolo[2,3-c]azepine derivatives was synthesized and evaluated as alpha1-adrenergic- and serotonin 2 (5-HT2)-receptor antagonists, with the aim of finding a novel potent antihypertensive agent with both activities. Among the compounds obtained in this study, (E)-1-ethyl-7-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hy droxyimino-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-on e (16d) displayed potent alpha1-adrenoceptor blocking activity (pA2=7.83+/-0.20) and 5-HT2-receptor blocking activity (pA2=9.47+/-0.17) in isolated guinea pig arteries. At 3 mg/kg oral administration, compound 16d exhibited antihypertensive activity more potent than that of doxazosin in deoxycorticosterone acetate (DOCA)-salt hypertensive dogs. Furthermore, this compound reduced the rate of mouse acute pulmonary thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or more, and its effect lasted for at least 6 h at 3 mg/kg.

Adrenergic alpha-1 Receptor Antagonists↗